Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rebecca Sims; Sven J van der Lee; Adam C Naj; Céline Bellenguez; Nandini Badarinarayan; Johanna Jakobsdottir; Brian W Kunkle; Anne Boland; Rachel Raybould; Joshua C Bis; Eden R Martin; Benjamin Grenier-Boley; Stefanie Heilmann-Heimbach; Vincent Chouraki; Amanda B Kuzma; Kristel Sleegers; Maria Vronskaya; Agustin Ruiz; Robert R Graham; Robert Olaso; Per Hoffmann; Megan L Grove; Badri N Vardarajan; Mikko Hiltunen; Markus M Nöthen; Charles C White; Kara L Hamilton-Nelson; Jacques Epelbaum; Wolfgang Maier; Seung-Hoan Choi; Gary W Beecham; Cécile Dulary; Stefan Herms; Albert V Smith; Cory C Funk; Céline Derbois; Davide Seripa; Gianfranco Spalletta; Paola Bossù; Chiara Fenoglio; Maria Serpente; Marina Arcaro; Carlo Caltagirone; Maria Donata Orfei; Antonio Ciaramella; Sandro Sorbi; Paolo Bosco; Daniela Galimberti; Elio Scarpini; Antonio Daniele; ARUK Consortium

doi:10.1038/ng.3916

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rebecca Sims, Sven J van der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert OlasoPer Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Davide Seripa, Gianfranco Spalletta, Paola Bossù, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sandro Sorbi, Paolo Bosco, Daniela Galimberti, Elio Scarpini, Antonio Daniele, ARUK Consortium

Research output: Contribution to journal › Article › peer-review

Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Original language	English
Pages (from-to)	1373-1384
Number of pages	12
Journal	Nature Genetics
Volume	49
Issue number	9
DOIs	https://doi.org/10.1038/ng.3916
Publication status	Published - Sep 2017

Keywords

Adaptor Proteins, Signal Transducing
Alzheimer Disease
Amino Acid Sequence
Case-Control Studies
Exome
Gene Expression Profiling
Gene Frequency
Genetic Predisposition to Disease
Genotype
Humans
Immunity, Innate
Linkage Disequilibrium
Membrane Glycoproteins
Microglia
Odds Ratio
Phospholipase C gamma
Polymorphism, Single Nucleotide
Protein Interaction Maps
Receptors, Immunologic
Sequence Homology, Amino Acid
Journal Article

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10.1038/ng.3916

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Sims, R., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., Raybould, R., Bis, J. C., Martin, E. R., Grenier-Boley, B., Heilmann-Heimbach, S., Chouraki, V., Kuzma, A. B., Sleegers, K., Vronskaya, M., Ruiz, A., Graham, R. R., ... ARUK Consortium (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics, 49(9), 1373-1384. https://doi.org/10.1038/ng.3916

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. / Sims, Rebecca; van der Lee, Sven J; Naj, Adam C; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W; Boland, Anne; Raybould, Rachel; Bis, Joshua C; Martin, Eden R; Grenier-Boley, Benjamin; Heilmann-Heimbach, Stefanie; Chouraki, Vincent; Kuzma, Amanda B; Sleegers, Kristel; Vronskaya, Maria; Ruiz, Agustin; Graham, Robert R; Olaso, Robert; Hoffmann, Per; Grove, Megan L; Vardarajan, Badri N; Hiltunen, Mikko; Nöthen, Markus M; White, Charles C; Hamilton-Nelson, Kara L; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W; Dulary, Cécile; Herms, Stefan; Smith, Albert V; Funk, Cory C; Derbois, Céline; Seripa, Davide; Spalletta, Gianfranco ; Bossù, Paola; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina ; Caltagirone, Carlo; Orfei, Maria Donata; Ciaramella, Antonio; Sorbi, Sandro; Bosco, Paolo; Galimberti, Daniela ; Scarpini, Elio ; Daniele, Antonio; ARUK Consortium.

In: Nature Genetics, Vol. 49, No. 9, 09.2017, p. 1373-1384.

Research output: Contribution to journal › Article › peer-review

Sims, R, van der Lee, SJ, Naj, AC, Bellenguez, C, Badarinarayan, N, Jakobsdottir, J, Kunkle, BW, Boland, A, Raybould, R, Bis, JC, Martin, ER, Grenier-Boley, B, Heilmann-Heimbach, S, Chouraki, V, Kuzma, AB, Sleegers, K, Vronskaya, M, Ruiz, A, Graham, RR, Olaso, R, Hoffmann, P, Grove, ML, Vardarajan, BN, Hiltunen, M, Nöthen, MM, White, CC, Hamilton-Nelson, KL, Epelbaum, J, Maier, W, Choi, S-H, Beecham, GW, Dulary, C, Herms, S, Smith, AV, Funk, CC, Derbois, C, Seripa, D, Spalletta, G , Bossù, P, Fenoglio, C, Serpente, M, Arcaro, M , Caltagirone, C, Orfei, MD, Ciaramella, A, Sorbi, S, Bosco, P, Galimberti, D , Scarpini, E , Daniele, A & ARUK Consortium 2017, 'Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease', Nature Genetics, vol. 49, no. 9, pp. 1373-1384. https://doi.org/10.1038/ng.3916

Sims, Rebecca ; van der Lee, Sven J ; Naj, Adam C ; Bellenguez, Céline ; Badarinarayan, Nandini ; Jakobsdottir, Johanna ; Kunkle, Brian W ; Boland, Anne ; Raybould, Rachel ; Bis, Joshua C ; Martin, Eden R ; Grenier-Boley, Benjamin ; Heilmann-Heimbach, Stefanie ; Chouraki, Vincent ; Kuzma, Amanda B ; Sleegers, Kristel ; Vronskaya, Maria ; Ruiz, Agustin ; Graham, Robert R ; Olaso, Robert ; Hoffmann, Per ; Grove, Megan L ; Vardarajan, Badri N ; Hiltunen, Mikko ; Nöthen, Markus M ; White, Charles C ; Hamilton-Nelson, Kara L ; Epelbaum, Jacques ; Maier, Wolfgang ; Choi, Seung-Hoan ; Beecham, Gary W ; Dulary, Cécile ; Herms, Stefan ; Smith, Albert V ; Funk, Cory C ; Derbois, Céline ; Seripa, Davide ; Spalletta, Gianfranco ; Bossù, Paola ; Fenoglio, Chiara ; Serpente, Maria ; Arcaro, Marina ; Caltagirone, Carlo ; Orfei, Maria Donata ; Ciaramella, Antonio ; Sorbi, Sandro ; Bosco, Paolo ; Galimberti, Daniela ; Scarpini, Elio ; Daniele, Antonio ; ARUK Consortium. / Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. In: Nature Genetics. 2017 ; Vol. 49, No. 9. pp. 1373-1384.

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title = "Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease",

abstract = "We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.",

keywords = "Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Exome, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Linkage Disequilibrium, Membrane Glycoproteins, Microglia, Odds Ratio, Phospholipase C gamma, Polymorphism, Single Nucleotide, Protein Interaction Maps, Receptors, Immunologic, Sequence Homology, Amino Acid, Journal Article",

author = "Rebecca Sims and {van der Lee}, {Sven J} and Naj, {Adam C} and C{\'e}line Bellenguez and Nandini Badarinarayan and Johanna Jakobsdottir and Kunkle, {Brian W} and Anne Boland and Rachel Raybould and Bis, {Joshua C} and Martin, {Eden R} and Benjamin Grenier-Boley and Stefanie Heilmann-Heimbach and Vincent Chouraki and Kuzma, {Amanda B} and Kristel Sleegers and Maria Vronskaya and Agustin Ruiz and Graham, {Robert R} and Robert Olaso and Per Hoffmann and Grove, {Megan L} and Vardarajan, {Badri N} and Mikko Hiltunen and N{\"o}then, {Markus M} and White, {Charles C} and Hamilton-Nelson, {Kara L} and Jacques Epelbaum and Wolfgang Maier and Seung-Hoan Choi and Beecham, {Gary W} and C{\'e}cile Dulary and Stefan Herms and Smith, {Albert V} and Funk, {Cory C} and C{\'e}line Derbois and Davide Seripa and Gianfranco Spalletta and Paola Boss{\`u} and Chiara Fenoglio and Maria Serpente and Marina Arcaro and Carlo Caltagirone and Orfei, {Maria Donata} and Antonio Ciaramella and Sandro Sorbi and Paolo Bosco and Daniela Galimberti and Elio Scarpini and Antonio Daniele and {ARUK Consortium}",

year = "2017",

month = sep,

doi = "10.1038/ng.3916",

language = "English",

volume = "49",

pages = "1373--1384",

journal = "Nature Genetics",

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T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

AU - Sims, Rebecca

AU - van der Lee, Sven J

AU - Naj, Adam C

AU - Bellenguez, Céline

AU - Badarinarayan, Nandini

AU - Jakobsdottir, Johanna

AU - Kunkle, Brian W

AU - Boland, Anne

AU - Raybould, Rachel

AU - Bis, Joshua C

AU - Martin, Eden R

AU - Grenier-Boley, Benjamin

AU - Heilmann-Heimbach, Stefanie

AU - Chouraki, Vincent

AU - Kuzma, Amanda B

AU - Sleegers, Kristel

AU - Vronskaya, Maria

AU - Ruiz, Agustin

AU - Graham, Robert R

AU - Olaso, Robert

AU - Hoffmann, Per

AU - Grove, Megan L

AU - Vardarajan, Badri N

AU - Hiltunen, Mikko

AU - Nöthen, Markus M

AU - White, Charles C

AU - Hamilton-Nelson, Kara L

AU - Epelbaum, Jacques

AU - Maier, Wolfgang

AU - Choi, Seung-Hoan

AU - Beecham, Gary W

AU - Dulary, Cécile

AU - Herms, Stefan

AU - Smith, Albert V

AU - Funk, Cory C

AU - Derbois, Céline

AU - Seripa, Davide

AU - Spalletta, Gianfranco

AU - Bossù, Paola

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Arcaro, Marina

AU - Caltagirone, Carlo

AU - Orfei, Maria Donata

AU - Ciaramella, Antonio

AU - Sorbi, Sandro

AU - Bosco, Paolo

AU - Galimberti, Daniela

AU - Scarpini, Elio

AU - Daniele, Antonio

AU - ARUK Consortium

PY - 2017/9

Y1 - 2017/9

N2 - We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

AB - We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

KW - Adaptor Proteins, Signal Transducing

KW - Alzheimer Disease

KW - Amino Acid Sequence

KW - Case-Control Studies

KW - Exome

KW - Gene Expression Profiling

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Immunity, Innate

KW - Linkage Disequilibrium

KW - Membrane Glycoproteins

KW - Microglia

KW - Odds Ratio

KW - Phospholipase C gamma

KW - Polymorphism, Single Nucleotide

KW - Protein Interaction Maps

KW - Receptors, Immunologic

KW - Sequence Homology, Amino Acid

KW - Journal Article

U2 - 10.1038/ng.3916

DO - 10.1038/ng.3916

M3 - Article

C2 - 28714976

VL - 49

SP - 1373

EP - 1384

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Abstract

Keywords

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